Protein Carbamylation and the Risk of ESKD in Patients with CKD

Abstract

Significance Statement Protein carbamylation, a nonenzymatic post-translational protein modification partially driven by elevated blood urea levels, associates with mortality and adverse outcomes in patients with ESKD on dialysis. However, little is known about carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. In this prospective observational cohort study of 3111 individuals with CKD stages 2–4, higher levels of carbamylated albumin (a marker of protein carbamylation burden) were associated with a greater risk of developing ESKD and other significant adverse clinical outcomes. These findings indicate that protein carbamylation is an independent risk factor for CKD progression. They suggest that further study of therapeutic interventions to prevent or reduce carbamylation is warranted. Background Protein carbamylation, a post-translational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in ESKD. However, little is known about protein carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. Methods To test associations between protein carbamylation and the primary outcome of progression to ESKD, we measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2–4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study. Results The mean age of study participants was 59 years (SD 10.8); 1358 (43.7%) were female, and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/minute per 1.73 m2, and the median C-Alb value was 7.8 mmol/mol (interquartile range, 5.8–10.7). During an average of 7.9 (4.1) years of follow-up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb ≤5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. The results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR. Conclusions Having a higher level of protein carbamylation as measured by circulating C-Alb is an independent risk factor for ESKD in individuals with CKD stages 2–4. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_24_JSN_URE_EP22_042423.mp3

Carbamylation in Uremia

“…Drug hypersensitivity, autoimmune disease, 2 infections, or systemic disease 3 can cause ATIN, or it can be idiopathic. Although members of families with ATIN share histological features and clinical symptoms, 4 designing a large-scale genetic study has been challenging because diagnosis requires kidney biopsy. To date, only candidate gene studies of ATIN have been performed.…”

“…Cyanate has known toxicity, and urea seems to have some modest toxicity; however, serum or BUN values are often used as a criterion for starting chronic hemodialysis. 4 Thus, the correlation of carbamylated albumin with ESKD may merely reflect the association of urea values with dialysis initiation.…”

The Microbiome and Protein Carbamylation: Potential Targets for Protein-Restricted Diets Supplemented with Ketoanalogues in Predialysis Chronic Kidney Disease

“…While the majority of epidemiological carbamylation studies have focused on ESKD patients [ 39 , 40 , 41 , 42 ], Kalim et al investigated the association between carbamylation load and CKD progression and mortality in pre-dialysis CKD patients. In two studies, levels of carbamylated albumin were found to be predictive of CKD progression and mortality independent of established predictors such as eGFR and proteinuria [ 43 , 44 ].…”

Comparative CKD risk prediction using homocitrulline and carbamylated albumin: two circulating markers of protein carbamylation

“…Epidemiological studies have shown that carbamylation is an independent risk factor for mortality and CKD progression [13][14][15][16][17][18][19][20][21]. Despite growing attention to carbamylation as a marker of and potential therapeutic target for adverse outcomes in CKD, the optimal assay to measure carbamylation burden remains to be determined.…”

“…Two different large scale studies recently measured C-Alb and HCit among participants of the Chronic Renal Insufficiency Cohort (CRIC) study, providing a unique opportunity to now compare head-to-head the operating characteristics and prognostic utility of two of the most widely used markers of carbamylation in clinical investigation [20,21]. In the present study, we aimed to test the hypothesis that baseline levels of C-Alb and HCit demonstrate similar operating characteristics: Specifically, we postulated that the adjusted hazard ratios, when linked to Fig.…”